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New Insights in Breast Cancer: Independent Conference Coverage of SABCS 2020

Sara Hurvitz, MD, FACP
Joyce O'Shaughnessy, MD
Released: February 19, 2021

Treatment De-Escalation Strategies in Hormone Receptor–Positive/HER2-Negative EBC

PRIME II 10-Year Update: Adjuvant Endocrine Therapy With or Without Radiotherapy After Surgery in EBC

Joyce O’Shaughnessy, MD:
At SABCS, we saw 10‑year follow-up from the randomized phase III PRIME II trial, which sought to answer an important clinical question about whether some older women can forego whole breast irradiation after surgery. The trial enrolled 1326 patients 65 years of age or older with hormone receptor–positive/node‑negative EBC.[6,7] Patients were randomized to receive adjuvant ET with or without whole breast irradiation. The primary endpoint of ipsilateral breast cancer recurrence was initially reported at 5 years of median follow-up, which is short for this biology of breast cancer. At that time, without radiation, there was a 4.1% risk of in‑breast tumor recurrence (IBTR) vs 1.3% with radiation (P = .0002).[6] Now, we have 10‑year data.

PRIME II 10-Year Update: Efficacy Outcomes

Joyce O’Shaughnessy, MD:
The primary endpoint analysis showed that IBTR with radiation therapy was 0.9% compared with 9.8% without radiotherapy (P = .00008). Hence, we see approximately 1% IBTR per year even in this favorable-risk group of patients with up to 3 cm of hormone receptor–positive breast cancer on ET with clear margins, and that rate is dramatically reduced with the addition of radiation therapy. The 10 year metastasis free survival was very good without radiation therapy, 98% compared with 96% with radiation, and there was no difference in death rate.

These are very mature data and they corroborate other data from the CALGB 9343 trial.[8] The IBTR rate is higher without radiation therapy, despite receiving ET, but the chances of dying of breast cancer are very low. Therefore, many women, particularly those with substantial comorbidities and/or shorter anticipated lifespans, would accept a 90% chance of remaining IBTR free at 10 years and forego the radiation therapy. For younger patients, I think we need to consider what might happen after 20 years of follow-up for this indolent type of breast cancer. Will it be a 20% IBTR rate at 20 years? We do not know. But for those women with a longer expected life span, it may make more sense to have radiation therapy. That is particularly true considering the partial breast and accelerated whole breast irradiation strategies that we now have available, as these can drastically decrease the radiation treatment time.

PRIME II 10-Year Update: Clinical Implications

Joyce O’Shaughnessy, MD:
To summarize, for younger and healthier women, we tend to recommend radiation therapy. But if a woman is older with a more limited life span because of comorbidities, then we would forego the radiation and monitor them closely because even if they did have an IBTR, the chances of having it cause substantial issues either locally or with metastatic disease is exceedingly low. It is a nice option to have with the right patients.

Sara Hurvitz, MD, FACP:
The PRIME data add support for omitting radiation in select patients: older than 64 years with endocrine receptor–positive, lymph node–negative tumors ≤ 3 cm with clear margins. That said, I would be reluctant to apply these data in patients with high‑grade tumors or low endocrine receptor expression; this study did appear to indicate a higher risk of recurrence when endocrine receptor expression is lower (P = .007). I think it is important for patients to understand, if they are omitting radiation therapy, they are taking on an increased risk of IBTR. However, this is unlikely to impact long‑term outcomes.

RxPONDER: Adjuvant ET With or Without Chemotherapy in Hormone Receptor+/HER2- EBC With 1-3 Positive Lymph Nodes and RS ≤ 25

Joyce O’Shaughnessy, MD:
The randomized phase III RxPONDER trial was probably the most anticipated presentation at SABCS 2020. In this trial, 5015 patients with hormone receptor–positive/HER2-negative EBC with a recurrence score ≤ 25 and 1‑3 positive lymph nodes with no distant metastases were randomized to receive chemotherapy followed by ET vs ET alone.[9] The primary endpoint was iDFS.

RxPONDER: iDFS (Primary Endpoint)

Joyce O’Shaughnessy, MD:
At a median follow-up of 5.1 years, there was a modest 1.4% improvement in iDFS that was statistically significant in favor of the chemotherapy/ET arm (HR: 0.81; P = .026). Of interest, whereas the recurrence score is predictive of chemotherapy benefit in patients with in node negative, hormone receptor positive breast cancer, we did not see that relationship in RxPONDER. The higher recurrence scores did not predict relative chemotherapy benefit for iDFS. However, recurrence score and chemotherapy use were independent prognostic factors for iDFS, with iDFS events less likely among patients who received chemotherapy and more likely among patients with higher recurrence scores.

RxPONDER: Prespecified Analysis by Menopausal Status

Joyce O’Shaughnessy, MD:
In a prespecified analysis by menopausal status, there was a statistically significant interaction between menopausal status and chemotherapy (P = .008).

RxPONDER: Baseline Characteristics by Menopausal Status

Joyce O’Shaughnessy, MD:
Looking at the baseline characteristics by menopausal status, the 1665 premenopausal patients were primarily younger than 50 years of age with higher recurrence scores (61% had recurrence scores 14-25). Meanwhile, the 3350 postmenopausal patients were primarily older than 50 years of age with a little more even distribution of lower and higher recurrence scores (44.8% vs 55.2%).

RxPONDER: iDFS by Menopausal Status

Joyce O’Shaughnessy, MD:
Just as we saw in the TAILORx trial as well as the MINDACT trial, there was no benefit of adding chemotherapy among postmenopausal women with recurrence scores of 0-25.[10,11] However, among premenopausal women, there was an absolute improvement in iDFS of 5.2% in favor of chemotherapy and the HR was quite striking (HR: 0.54; P = .0004). Moreover, the absolute difference in distant recurrence as a first site of recurrence was 2.9% among premenopausal women. Thus, the benefit from adding chemotherapy to ET was entirely in the premenopausal group.

RxPONDER: iDFS by Menopausal Status Across Subgroups

Joyce O’Shaughnessy, MD:
A similar benefit of adding chemotherapy was seen across subgroups of the premenopausal population. Of interest, an exception was in women 50 years of age or older, where the HR was only 0.84 compared with 0.43 and 0.44 in women younger than 50 years of age. This suggests that the likelihood of chemotherapy benefit is greater among women who have more ovarian function, which is really quite interesting.

RxPONDER: iDFS by RS and Menopausal Status

Joyce O’Shaughnessy, MD:
What about premenopausal women with the lowest recurrence scores of 0-13? They still had a 3.9% absolute improvement in iDFS with chemotherapy. The absolute difference was even higher for premenopausal women with recurrence scores of 14-25, at 6.2%. By contrast, postmenopausal women had no benefit of chemotherapy regardless of recurrence scores. They did very well with ET alone, but adding chemotherapy did not lead to an additional benefit.

RxPONDER: iDFS by Number of Nodes and Menopausal Status

Joyce O’Shaughnessy, MD:
Regarding lymph node involvement, premenopausal women with 1 positive node had a 5.2% absolute improvement in iDFS with chemotherapy. The absolute difference was almost identical among those with 2-3 nodes positive. Among postmenopausal women, again, there was no benefit from adding chemotherapy regardless of the number of positive nodes.

RxPONDER: OS by Menopausal Status

Joyce O’Shaughnessy, MD:
OS benefit from adding chemotherapy to ET also favored the premenopausal population. We need longer follow-up, but the 5‑year OS rate was 1.3% higher when chemotherapy was added in the premenopausal group (98.6% vs 97.3%), and the HR was 0.47, with a P value of .032. Certainly, these data are very intriguing, and I think it will be prudent to wait for longer data, but it does suggest that there may be a survival impact of chemotherapy in this premenopausal group with 1-3 nodes positive.

RxPONDER: Clinical Implication

Joyce O’Shaughnessy, MD:
To summarize, in the RxPONDER trial, we saw a clear result that postmenopausal women with 1-3 positive lymph nodes and recurrence scores of 0-25 can safely be spared adjuvant chemotherapy. There is no benefit, even among those with higher recurrence scores or with 2‑3 nodes positive.

By contrast, there is a substantial benefit from adding chemotherapy for the premenopausal group of patients regardless of recurrence score (up to 25), including a possible impact on survival.

These data make me wonder if a luteinizing hormone-releasing hormone (LHRH) agonist would be just as beneficial as chemotherapy in the premenopausal patients, because we know that only 16% of premenopausal patients in the RxPONDER trial received an LHRH agonist as part of their ET since the SOFT and TEXT data were not available at the time this study was conceived.[12] If the premenopausal patients had received an LHRH agonist that stopped ovarian function, would they have needed the chemotherapy, that is, would they have become more like the postmenopausal population? From a practical standpoint, when a woman has 1-3 nodes positive and a lower recurrence score (eg, 0-13) and has very indolent biology, such as strong hormone receptor–positivity, grade 1/2, and a lower Ki-67 (< 15%), I think it is reasonable to discuss an LHRH agonist with the patient as well as an aromatase inhibitor—that is, give her the optimal ET. It would be great to have another randomized trial comparing chemotherapy with ET with ET alone where all premenopausal patients are receiving an LHRH agonist. I suspect that the chemotherapy is having mainly an ET effect.

Sara Hurvitz, MD, FACP:
The RxPONDER data are indeed practice changing. We can now, I believe, safely omit chemotherapy for patients with 1-3 positive lymph nodes and a recurrence score < 25, especially if the patient is postmenopausal. Where it becomes a little trickier is for premenopausal women, where the data are a little less clear, there does appear to be a real benefit with the use of chemotherapy in premenopausal women with node‑positive disease regardless of recurrence score.

That said, I agree with Dr. O’Shaughnessy that ovarian suppression may yield similar outcomes to that seen with chemotherapy in these premenopausal patients; this remains an unanswered question. I think clinicians are still going to need to wrestle with these data on a case-by-case basis regarding the use of chemotherapy in our younger premenopausal or perimenopausal women.

ADAPT HR+/HER2-: Adjuvant ET With or Without Chemotherapy in Intermediate-/High-Risk, Hormone Receptor+/HER2- Luminal EBC

Joyce O’Shaughnessy, MD:
The phase III ADAPT HR+/HER2- trial is a very interesting trial designed to evaluate the prognostic impact of recurrence score and Ki-67 expression after a short-course of preoperative ET in patients with hormone receptor–positive/HER2-negative unilateral, luminal EBC with clinical T1 to T4c disease who were candidates for adjuvant chemotherapy (N = 4691).[13] Participants underwent a baseline biopsy for diagnosis to determine a recurrence score and Ki-67 expression level. Then, all participants received 2-4 weeks of preoperative ET followed by their definitive surgery, where Ki-67 was evaluated again.

The current analysis is part 1, in which patients who, following preoperative ET, had pN0-1 with a recurrence score of 12-25 and Ki-67 ≤ 10% or pN0-1 and a recurrence score between 0 and 11 were assigned to receive adjuvant ET alone. This is not a randomized comparison. The primary endpoint was 5‑year iDFS.

The question is whether the preoperative ET response can identify patients who do not need adjuvant chemotherapy.

ADAPT HR+/HER2-: 5-Year iDFS (Primary Endpoint)

Joyce O’Shaughnessy, MD:
The primary endpoint of this trial was met. Both groups that received adjuvant ET alone had excellent 5 year iDFS (93% to 94%). It was equivalent between patients in the most favorable risk profile, that is, those who had a recurrence score of 0-11, and those who suppressed Ki-67 to 10% or less who had a recurrence score of 12-25. OS at 5 years was also excellent at 97% to 98%.

ADAPT HR+/HER2-: 5-Year dDFS

Joyce O’Shaughnessy, MD:
Similar 5-year distant DFS (dDFS) outcomes were seen whether patients were older than 50 years of age or younger. The only group that did not do as well with ET alone was patients with 3 positive nodes who had higher recurrence scores (12-25) and suppressed their Ki-67 with preoperative ET. In that subgroup, 75.9% were alive and free of distant disease at 5 years compared with 100% of patients with 3 positive nodes and pathologic N0-N1 plus recurrence scores of 0-11. Among patients with 2 positive nodes, 5-year dDFS in patients who suppressed Ki-67 was 3.6% higher in those with a low recurrence score (0-11) compared to those with a recurrence score of 12-25.

Based on these data, when considering whether to add chemotherapy to ET in the adjuvant setting, I think we would factor in a patient’s Ki-67 expression after 2-4 weeks of preoperative ET. If it is suppressed to < 10% and they are node negative or have 1 positive node, that is quite favorable and predicts for an excellent outcome without adding chemotherapy.

ADAPT HR+/HER2-: Clinical Implications

Joyce O’Shaughnessy, MD:
Unlike the findings from the TAILORx trial (node-negative patients) and the RxPONDER trial (patients with 1-3 positive nodes) that show benefit from adjuvant chemotherapy in premenopausal women, the ADAPT- HR+/HER2- trial demonstrates that premenopausal women with a recurrence score ≤ 25 and 0 to 2 nodes positive, and who suppress Ki-67 with preop ET, have an excellent outcome without adjuvant chemotherapy. I would be curious to implement this strategy from the ADAPT trial and give premenopausal patients ET prior to surgery and see if they suppress Ki-67. This could be particularly helpful for those patients for whom you wonder whether they will benefit from chemotherapy, such as someone with 100% hormone-receptor positivity, grade 1/2 tumor, and Ki-67 < 15%. This strategy is being strongly advocated in Germany, and I am interested to see if we will do the same in the United States.

Sara Hurvitz, MD, FACP:
ADAPT- HR+/HER2- is an elegantly designed study indicating a means of identifying a group of patients with 1-3 positive nodes or an intermediate recurrence score who might not benefit from adjuvant chemotherapy. However, using Ki-67 changes in the neoadjuvant setting before and after treatment in routine clinical practice has its challenges, so uptake may be quite limited, especially in community practices.

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